(E)-2,4,6-trimethoxystyryl-3-[(carboxymethyl)amino]-4-methoxybenzylsulphone and pharmaceutically acceptable salts thereof, is an antiproliferative agent that targets receptor tyrosine kinases and which arrest the Ras/Raf/MEK/ERK kinase cascade. The sodium salt is known as Rigosertib and ON 01910.Na and is described in U.S. Pat. No. 8,063,109 B2, U.S. Pat. No. 8,476,320 B2, and U.S. Pat. No. 7,598,232 B2.
Rigosertib is a drug candidate and has been formulated with water soluble polymers such as PEG 400, and with aqueous buffers, as described in U.S. Pat. No. 8,476,320 B2. However, these formulations lead to unacceptable levels of impurities. In particular, vials containing Rigosertib and PEG 400 show unacceptable levels of impurities in a matter of months when stored at room temperature and thus such vials must be stored under refrigeration, which is not convenient and adds expense. In addition, Rigosertib in 100% PEG 400, NF when administered via infusion bags can degrade over the course of long infusion periods reducing the ability to accurately deliver the drug. Also, vials containing Rigosertib, PEG 400, and phosphate buffer at high pH may form crystals. Thus, there is a need for pharmaceutical compositions with enhanced stability for oral and parenteral administration. There is also a need for pharmaceutical compositions with improved oral bioavailability.
When administered orally, a common adverse event is urothelial toxicity. Bowles, et al., Clin. Cancer Res. 2014 Mar. 15; 20(6): 1656-1665. Thus, there is also a need for a method of administering Rigosertib in a manner that reduces urothelial toxicity.
The present invention is predicated, at least in part, by the discovery that the Rigosertib solutions in polyethylene glycol solutions having an undiluted pH of about 11.0 to about 14.0 had surprisingly improved stability and impurity levels. These pharmaceutical compositions were also found to have surprisingly good oral bioavailability characteristics.